ARNT PROTEIN FUNCTION IN ANGIOGENESIS AND HEMATOPOIESIS

ARNT 蛋白在血管生成和造血中的功能

• 批准号: 6363585
• 负责人: M. CELESTE SIMON
• 金额: $ 29.97万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-15 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6363585
• 关键词: angiogenesis; athymic mouse; developmental genetics; erythropoietin; gene induction /repression; genetically modified animals; hematopoiesis; hypoxia; immunocytochemistry; in situ hybridization; p53 gene /protein; protein structure function; teratoma; transcription factor; vascular endothelial growth factors

DESCRIPTION (Verbatim from investigator's abstract): Angiogenesis and hematopoiesis are functionally related processes that generate the vessels and blood cells of the circulatory system. Recent data have demonstrated that oxygen deprivation (hypoxia), in addition to developmentally regulated signals, is a potent activator of angiogenesis and hematopoiesis. To investigate the molecular mechanisms whereby hypoxia regulates these processes, mutations have been generated in the murine Arnt gene, which encodes a bHLH-PAS transcription factor. ARNT protein regulates the expression of Epo, VEGF and other angiogenesis-related genes through interactions with its heterodimeric partner, HIF-1alpha. Arnt -/- ES cells fail to upregulate may target genes under hypoxic conditions, and Arnt-/- mutant embryos are arrested in development at embryonic day E9.5-10.5, apparently due to vascular abnormalities in the placenta, yolk sac and embryo itself. More recently, it has been shown that the Arnt -/- mutation also disrupts normal hematopoiesis in yolk sac blood islands. A second, highly related murine Arnt gene (Arnt 2) has recently been described. Although expressed in a strikingly different spatial pattern than Arnt 1 in embryonic and adult mice, it is possible that Arnt 2 may partly compensate for the loss of the Arnt protein in Arnt -/- mutant embryos. It is proposed to generate and analyze Arnt 2 -/- and Arnt -/-, Arnt 2-/- double mutant mouse strains, which will address many important questions regarding the role of both Arnt and Arnt2 in mediating hypoxia-induced angiogenesis and hematopoiesis. As hypoxic responses are more important in a variety of pathologies, including post-ischemic neovascularization and tumor cell apoptosis, the results of these experiments should prove valuable in developing clinical approaches in the future. At a basic level, they will provide important information oon hypoxia-induced transcriptional regulation that complements our rapidly expanding understanding of receptor/ ligand signalling in angiogenesis and hematopoiesis.

描述（逐字摘自研究者摘要）：血管生成和 造血是产生血管的功能相关过程， 循环系统的血细胞。最近的数据表明， 缺氧（缺氧），除了发育调节信号， 是血管生成和造血的有效激活剂。探讨 缺氧调节这些过程的分子机制，突变具有 在编码bHLH-PAS转录的鼠Arnt基因中产生 因子ARNT蛋白调节Epo、VEGF和其他细胞因子的表达。 通过与其异源二聚体配偶体的相互作用， 缺氧诱导因子-1 α。Arnt -/- ES细胞在缺氧条件下不能上调可能的靶基因 条件下，Arnt-/-突变胚胎在胚胎发育中被阻止， E9.5-10.5天，显然是由于胎盘、卵黄 胚囊和胚本身。最近，已经表明Arnt -/- 突变还破坏卵黄囊血岛中的正常造血。一 其次，最近描述了高度相关的鼠Arnt基因（Arnt 2）。 虽然在一个与Arnt 1显著不同的空间模式中表达， 在胚胎和成年小鼠中，Arnt 2可能部分补偿了 Arnt -/-突变胚胎中Arnt蛋白的丢失。提出要 制备并分析Arnt 2 -/-和Arnt -/-、Arnt 2-/-双突变小鼠 菌株，这将解决许多重要的问题，关于双方的作用 Arnt和Arnt 2介导缺氧诱导的血管生成和造血。作为 缺氧反应在多种病理中更为重要，包括 缺血后新生血管和肿瘤细胞凋亡，这些结果 实验应该证明在开发临床方法方面是有价值的。 未来在基本层面上，它们将提供关于 缺氧诱导的转录调节，补充我们的迅速 扩大对血管生成中受体/配体信号传导的理解， 造血